Editorial

Segmental defects in peripheral nerves that cannot be sutured directly require the use of nerve
grafts. The ideal option for repair is nerve auto grafting, but there are some obvious disadvantages
related to its use, such as lack of availability and donor site morbidity. The next step to consider
for reconstruction is the use of nerve allografts, but they are also limited for clinical use, and they
present with the added problem of graft rejection. Considering these limitations to the use of nerve
autografts and allografts, clinical surgery research has turned to nerve xenotransplantation, which
offers a potentially unlimited source of donor nerves.
We conducted a review of the literature, aiming to clarify the present situation regarding
peripheral nerve xenotransplantation and to summarize the latest proposals and investigative
directions. The molecular and biochemical reactions involved in graft integration as well as the host
immune response to xenografts are at the center of current research.
A nerve graft acts as a biological scaffold that allows and directs axon regeneration. However, in
xenografts, immune rejection and the scar tissue that is formed due to the immune response inhibits
axon growth [1]. Of the main components of a peripheral nerve, Schwann cells — both host and
donor cells — are the critical elements for nerve regeneration and production of neurotropic factors,
but donor Schwann cells are one of the most immunogenic components of nerve grafts. To reduce
immune reaction, graft pretreatment to decrease antigenicity has been proposed; however, these
treatments also reduce Schwann cell viability [2]. Different methods have been described, but due
to the lack of satisfactory results recent research is leaving behind graft pretreatment and moving
towards other mechanisms of immune response suppression.
Many investigations have aimed to clarify the molecular components of graft rejection. Some
of the elements involved have been identified, such as interferon-gamma (IFy)-producing Th1 cells
and IL17-producing Th17 cells. Therefore, treatment with IL17 and IFy neutralizing antibodies
could reduce nerve xenograft rejection. Other proposed inhibitors of the immune response to nerve
xenografts have been brain-derived neurotrophic factor and immunosuppressive drugs FK506 and
RS61443 [3].
Studies show that higher doses are needed to achieve immunosuppression with xenografts than
those used with nerve allografts [4]. One study proposed that there is a limit distance of 7 mm to 8
mm that nerve regeneration through a xenograft is able to cover against acute host rejection without
immunosuppression [5].
Another approach to peripheral nerve repair is the use of biologic or synthetic nerve conduits,
which do not cause immune rejection and allow a reduction of donor site morbidity and surgery
time. A nerve conduit must be biocompatible and it must have the capacity to produce the
adequate molecular signals that promote cell differentiation, migration and axonal elongation
(neuroinductivity and neuroconductivity). To achieve neuroinductivity and neuroconductivity,
many groups have proposed different approaches. Some investigators use a synthetic or biological
nerve conduit with added host or xenogeneic multipotent stem cells. Bone marrow stromal cells
(BMSCs), human umbilical cord stromal cells (HUCSCs), undifferentiated and adipose-derived
stem cells have been studied. Zarbakhsh et al. [6] conducted a study in which 10 mm nerve gaps in
rats were bridged with a silicone conduit with added bone marrow stromal cells (BMSC), human
umbilical cord stromal cells (HCUCSCs) or no cells. He concluded that both auto-BMSCs and xenoUCSC
have the potential to regenerate peripheral nerve injury and that BMSCs are more effective
than HCUCSCs in rat. As opposed to other xenogeneic cells, stem cells did not seem to provoke an
immune response in the host after transplantation. Other groups have proposed the use of acellular xenografts.
Acellular xenografts are created by chemically eliminating the cellular
constituents that cause immunogenic reactions but preserving
the native extracellular matrix, which retains sufficient bioactivity
to promote axon regeneration [7]. Zhang et al. [8] reported that
acellular nerve xenografts, similarly to acellular nerve allografts,
are immunocompatible. They also proposed that short defects can
regenerate along acellular scaffolds but that longer defects might
require certain cellular impulses that should be provided by added
autologous stem cells. The results in terms of functional rehabilitation
efficacy of these grafts have been proved comparable to autografting
[9].
All present lines of investigation are limited to animal
experimentation. There is only one study in the literature that
includes human sural nerves as donor grafts and none with
humans as graft receptors. With organ transplantation, the risks of
immunosuppression are assumed due to urgent or life-threatening
situations. But this is not the case of peripheral nerve injuries and,
therefore, nerve xenografts could only be considered when the
risks associated to immunosuppression and even cross-species
disease transmission has been completely eliminated. Differences
have also been observed depending on the donor and host species
used; the reasons for these differences should be further studied and
understood before human investigations can be considered [10].
Another limitation is defect length. The longest defects repaired
successfully have been 40 mm [11].
Future research will move towards the perfection of existing
xenograft models, to create an acellular xenograft that is
immunocompatible, not requirig immunosuppressive therapy,
seeded with growth factor-producing elements such as xenogeneic
stem cells and that can be made to fit the length of the existing defect.